Steroid-resistant nephrotic syndrome (SRNS) is an infrequent kidney disorder marked by hypoalbuminemia, proteinuria, and often edema, with focal segmental glomerulosclerosis being the most common histological presentation. About 20 – 30% of SRNS cases are due to genetic causes, with variable outcomes ranging from remission to progression to end-stage kidney disease.
Genetic SRNS is highly heterogeneous, involving around 70 genes, with NPHS2 among the key genes. Mutations in NPHS2, which encodes the podocyte-specific protein podocin, disrupt the glomerular filtration barrier and lead to proteinuria. Over 240 pathogenic NPHS2 variants have been identified. This report presents a case of SRNS caused by a biallelic NPHS2 missense variant resulting from paternal uniparental disomy of chromosome 1 (UPD(1)pat). Uniparental disomy is a rare genetic mechanism, in which both chromosome copies are transmitted from one parent, potentially leading to homozygosity for recessive mutations.
Read more on detecting uniparental disomy (UPD) with Geneyx Analysis here
The affected individual is a Caucasian woman born to non-consanguineous parents who developed multidrug-resistant nephrotic syndrome at 5 months of age, requiring extensive treatment and ultimately a kidney transplant at age 6. Over the years, she experienced additional health challenges but remained stable with improved kidney function in adulthood. Given her desire for future parenthood and the absence of a prior genetic diagnosis, clinical exome sequencing was performed. Genomic DNA from the patient and her parents was analyzed using the ClinEX pro kit and NovaSeq6000 platform. The bioinformatic pipeline included DRAGEN Germline Pipeline and Geneyx Analysis software, which enabled efficient filtering and prioritization of variants. This analysis identified a homozygous pathogenic variant in the NPHS2 gene (c.413G>A, p.Arg138Gln) in the patient, which was also detected in a heterozygous state in the father. Further single nucleotide polymorphism (SNP) array analysis identified UPD(1)pat, confirming the genetic mechanism behind the patient’s autosomal recessive nephrotic syndrome.
In summary, this study explores the genetic cause of SRNS in a patient found to carry a homozygous NPHS2 c.413G>A variant, which disrupts podocin function. Although only the father was a heterozygous carrier, SNP-array analysis confirmed UPD(1)pat, likely due to a monosomy rescue event during embryogenesis. This rare mechanism can unmask recessive mutations inherited from a single parent. This analysis demonstrates the critical value of trio-based testing and parental segregation studies in uncovering such genetic events.
Take a look at the Geneyx Analysis: Version 6.1. New Features
